Several lines of evidence suggest that negative symptoms and working memory impairment in schizophrenia are associated with a dysfunction of the dorsolateral prefrontal cortex (DLPFC). In addition, preclinical and clinical data support the hypothesis that alterations in prefrontal dopamine (DA) and serotonin (5-HT) function may underlie these deficits. Decreased binding of the D1 receptor PET radiotracer, [11C]SCH 23390, has been reported in the prefrontal cortex of male patients with schizophrenia, suggesting that schizophrenia may be associated with a deficiency in D1 receptors in the DLPFC (1). Furthermore, a relationship between this decreased binding and the severity of working memory impairment was observed. We now proposed to extend this important finding to patients of both genders and to first episode/drug naive patients, suing a higher resolution PET camera, a more specific D1 radiotracer, [11C]NNC-112, and a more extensive neuropsychological battery. Groups will include 40 chronic untreated patients, 20 first episode/drug naive patients, and 60 matched healthy controls. In postmortem studies, the most replicated neurochemical finding in the prefrontal cortex of patients with schizophrenia is an increase in serotonin 5- HT1A receptor density. This finding has been observed in 7 out of 7 postmortem studies. The significance of this finding for the pathophysiology of schizophrenia remains clinical symptomatology, and assess the role of previous treatment by including drug naive patients. The second goal of this application is to measure prefrontal 5-HT1A receptor density in the same group of patients with schizophrenia using the PET radiotracer, [11C]WAY- 100635. D1 and 5-HT1A receptor function play a critical role in the modulation of pyramidal cells activity in the DLPFC. Recent postmortem studies revealed that schizophrenia is associated with reduced arborization and D1 receptor and increased 5-HT1A receptor density. By measuring D1 and 5-HT1A in the same patients, we will test the hypothesis that both abnormalities coexist and reflect a common alteration in the neurodevelopment of the DLPFC. This study will lead to a better understanding of neurochemical abnormalities in schizophrenia, their relations to symptomatology, and their implications for treatment.